This component investigates the hypothesis that metabolic abnormalities due to increased dosages of specific enzymes may cause some of the phenotypes seen in Down Syndrome, especially those affecting neurocognitive and sensorineural development and neurodegeneration. Chromosome 21 genes involved in the interrelated pathways of purine, folate, and reactive oxygen species (ROS) metabolism will be examine, because mutations in all these pathway lead to neurological deficits in humans. Transgenic and knockout mice altered to the purine and Ros pathways have developmental anomalies, including neurological deficits, consistent with the expected effects of alteration of the pathways and also consistent with the human phenotypes seen in individuals with mutations in the pathways. Transgenic mice expressing genes in the purine pathways have been obtained during the current funding period. Specific aims include: 1) characterization of the phenotypes of the transgenic mice already obtained; 2) creation of additional transgenic mice expressing the human ATP50 gene encoding a subunit of ATP synthase and the human gene for carbonyl reductase and analysis of these mice; 3) creation of Ts65Dn- uricase deficient partial trisomy 16 mouse to serve as a higher fidelity mouse model of human metabolism; 4) crossing the mice created in 4 with the reduced folate carrier transgenic mice and analysis of the effect of this on the phenotype of the Ts65Dn mouse; 5) creation and analysis of knockout mice for four of the genes (GART, ATP50, CBR, and SOD1) in the region trisomeric in the Ts65Dn mouse and appropriate breeding of these to determine the effect of restoring these genes to the normal diploid state; 6) analysis of the expression of the genes under study in brain samples from individuals with and without Down Syndrome; and 7) assessment of the role of urate on ROS metabolism by appropriate crosses of mice with alterations in the ROS pathway and the uricase deficient mice. These experiments should result in a rigorous understanding of the role of these pathways in cognition and neural development and whether trisomy of the genes in the pathway plays a role in DS.